Abstract
USP7 is a promising target for the development of cancer treatments because of its high expression and the critical functions of its substrates in carcinogenesis of several different carcinomas. Here, we demonstrated the effectiveness of targeting USP7 in advanced malignant cells showing high levels of USP7, especially in taxane-resistant cancer. USP7 knockdown effectively induced cell death in several cancer cells of lung, prostate, and cervix. Depletion of USP7 induced multiple spindle pole formation in mitosis, and, consequently, resulted in mitotic catastrophe. When USP7 was blocked in the paclitaxel-resistant lung cancer NCI-H460TXR cells, which has resistance to mitotic catastrophe, NCI-H460TXR cells underwent apoptosis effectively. Furthermore, combination treatment with the mitotic kinase PLK1 inhibitor volasertib and the USP7 inhibitor P22077 showed a strong synergism through down-regulation of MDR1/ABCB1 in paclitaxel-resistant lung cancer. Therefore, we suggest USP7 is a promising target for cancer therapy, and combination therapy with inhibitors of PLK1 and USP7 may be valuable for treating paclitaxel-resistant cancers, because of their strong synergism.
Highlights
80% of intracellular proteins are bound to ubiquitin, a labeling protein that signals for degradation by the proteasome complex that recognizes it
Our previous study revealed that Ubiquitin-specific-processing protease 7 (USP7) binds to the 53BP1/PLK1/Aurora A complex to stabilize 53BP1 during mitosis [2]
These observations lead us to hypothesize that targeting USP7 would be valuable for cancer treatment, especially in carcinomas that have resistance to mitotic catastrophe
Summary
80% of intracellular proteins are bound to ubiquitin, a labeling protein that signals for degradation by the proteasome complex that recognizes it. Ubiquitin-specific-processing protease 7 (USP7), one of the deubiquitinating enzymes, functions in the ubiquitin-proteasome machinery It regulates the stability of various proteins, thereby affecting their physiological functions in cells and playing a wide role in signal transduction processes in the cell cycle, and in the stress response, DNA repair, and apoptosis, depending on the cellular substrates and context [1,2,3,4,5,6,7,8]. It has been reported that overexpression of USP7 is closely related to the malignancy of prostate cancer [1] Based on these oncopathological characteristics, selective inhibitors against the catalytic activity of USP7 have been actively developed, such as HBX-41108 [16], P22077 [17], and P5091 [18,19]. Based on the current literature, pharmacological inhibitors of USP7 are promising anticancer agents in various carcinomas, depending on the cellular context
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